Invited Commentary Apolipoprotein B vs Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol as the Primary Measure of Apolipoprotein B Lipoprotein-Related Risk The Debate Is Over Allan D. Sniderman, MD; Ann Marie Navar, MD, PhD; George Thanassoulis, MD In 1979, Avogaro et al 1 reported that apolipoprotein B (apoB) was a more accurate marker of the risk of a myocardial in- farction than total cholesterol. In 1980, Sniderman et al 2 re- ported that low-density lipoprotein (LDL) apoB was a more accurate marker of the risk of angiographic coronary le- sions than LDL cholesterol (LDL-C). They inferred that the mass of cholesterol per apoB particle could vary and they speculated that the number of apoB particles mattered more than the cholesterol they con- tained because it was the particle that entered and was depos- ited within the arterial wall. 2 Since then, there has been con- siderable debate whether apoB, LDL-C, or non–high-density lipoprotein cholesterol (non-HDL-C) should be the primary measure of apoB lipoprotein-related risk. The debate is over. In this issue, Marston and colleagues 3 supply decisive evi- dence from a large, prospective observational study, UK Bio- bank, and 2 clinical trials, FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and IMPROVE-IT (Improved Reduction of Out- comes: Vytorin Efficacy International Trial), that apoB should be the primary marker to assess the cardiovascular risk due to the apoB lipoproteins. This line of thought has been driven as much by ad- vances in basic science as by epidemiology and clinical trials. The discovery of cholesterol ester transfer protein by Patt- naik et al 4 underpins the work by Krauss et al, 5 which showed that the cholesterol content of LDL particles varied. By con- trast, each apoB lipoprotein particle always has only a single apoB molecule; therefore, apoB equals atherogenic particle number. Because the mass of cholesterol per particle is vari- able, LDL-C and non-HDL-C can differ significantly from apoB. Because non-HDL-C and LDL-C are physiologically related and highly correlated with apoB, many have argued that LDL-C and non-HDL-C are “good enough” to measure lipoprotein- related risk. Meanwhile, evidence from prospective observa- tional studies, including discordance analyses, mendelian ran- domization studies, and studies in statin-treated patients, has mounted steadily in favor of using apoB over LDL-C and non- HDL-C to measure atherogenic risk of apoB lipoproteins. 6,7 Not only does apoB better predict risk than LDL-C or non- HDL-C, it also better predicts benefit from lipid-lowering therapy. The landmark study by Ference et al, 8 who applied mendelian randomization to simulate randomized clinical trials, demonstrated that reduction of equal numbers of very LDL and LDL particles produced equivalent clinical benefit. Johannesen et al 9 recently demonstrated that apoB was a more accurate marker of cardiovascular risk in statin-treated pa- tients than LDL-C or non-HDL-C. The present analysis by Mar- ston et al 3 should provide a final coup de grâce for LDL-C and non-HDL-C. Marston et al confirm that the hazard ratios of LDL-C, non- HDL-C, and apoB per standard deviation increase are virtu- ally identical in UK Biobank. 3 That the hazard ratio is similar does not mean they are equally useful in predicting risk. When cholesterol-depleted particles are present, the risk predicted by apoB will be higher than the risk predicted by LDL-C or non- HDL-C. The converse will be true when cholesterol-rich par- ticles are present. In their study, LDL-C and non-HDL-C be- come nonsignificant markers of risk when apoB is taken into account, demonstrating that the risk of LDL-C and non- HDL-C is fully captured by the number—not the cholesterol content—of the apoB-containing particles. 3 These findings are further supported by data from IMPROVE-IT, which randomized the addition of ezetimibe to statin therapy, and FOURIER, which randomized the addition of a PCSK9 in- hibitor to maximally tolerated statin therapy in patients with preexisting cardiovascular disease, that show apoB is a more accurate predictor of cardiovascular risk than LDL-C or non- HDL-C. Thus, there is now broad and consistent evidence from observational studies and post hoc analyses of randomized clinical trials, in both primary and secondary prevention, sup- porting the superiority of apoB. But there is another, just as critical, argument for apoB: apoB is far less prone to measurement error than LDL-C or non-HDL-C. The European Atherosclerosis Society/European Federation of Laboratory Medicine consensus report states that apoB can be measured inexpensively, and more accurately, than LDL-C or non-HDL-C, using standardized, automated, widely available methods that produce results as rapidly as a conventional lipid panel. 7 In contrast, accurate, standardized LDL-C measurement remains elusive, as evidenced by ongo- ing efforts to develop new equations to estimate LDL-C from a traditional lipid panel. 10 How can the decision about who to treat and how aggressively to treat be based on anything but the most reliable and accurate test available? What is the argument for selecting patients for therapies based on a less reliable and less accurate test when a superior alternative is available? Yes, LDL-C has been the primary marker of clinical effec- tiveness reported in the major randomized controlled clinical trials of lipid-lowering therapy. But statins and PCSK9 inhibi- tors lower very LDL apoB particles as well as LDL apoB par- ticles. Therefore, LDL-C is an incomplete marker of the ben- efit of statin, ezetimibe, or PCSK9 therapy. Others have proposed using non-HDL-C instead of LDL-C. But non- Related article ApoB vs LDL-Cholesterol and Non-HDL-C as the Primary Measure of ApoB Lipoprotein-Related Risk Invited Commentary jamacardiology.com (Reprinted) JAMA Cardiology Published online November 13, 2021 E1 © 2021 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 11/15/2021